Pain in general is associated with a myriad of medical conditions and affects millions of Americans. As reported by the American Pain Foundation, over 50 million Americans suffer from chronic pain including 20% of individuals aged 60 and over who are affected by joint disorders such as arthritis. Furthermore, nearly 25 million Americans experience acute pain due to injuries or surgical procedures each year. In addition to its economical burden, pain has a tremendous effect on the quality of life of affected individuals and is one of the most common causes of disability.
Cell-adhesion interactions are crucial for a broad range of physiological processes, including inflammation, immunity, and hemostasis. Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localize within the extra-cellular matrix. Among fundamental mechanisms underlying numerous biological phenomena, cell adhesion is responsible for the adhesion of hematopoietic cells to endothelial cells and the subsequent migration of those hematopoietic cells out of blood vessels and to the site of inflammatory injury. As such, cell adhesion plays a role in numerous pathologies such as, for example, inflammation and immune reactions in mammals. In failed back syndrome, cell adhesion complicates revision surgeries and an effective method to decrease adhesive occurrence and tenacity would be beneficial. Particularly a method that involves a formula that reduces the pain tenacity is beneficial.
Investigations into the molecular basis for cell adhesion have revealed that various cell-surface macromolecules—collectively known as cell adhesion molecules or receptors—mediate cell-cell and cell-matrix interactions. For example, proteins of the superfamily called “integrins” are key mediators in adhesive interactions between hematopoietic cells and their micro environment. M. E. Hemler, “VLA Proteins in the Integrin Family: Structures, Functions, and Their Role on Leukocytes”, Ann. Rev. Immunol., 8, p. 365 (1990).
Alpha 4 beta1 integrin, also known as very late antigen of activation-4 (“VLA-4”) or CD49d/CD29, is a leukocyte cell surface receptor that participates in a wide variety of both cell-cell and cell-matrix adhesive interactions. M. E. Hemler, Ann. Rev. Immunol., 8, p. 365 (1990). It serves as a receptor for the cytokine-inducible endothelial cell surface protein, vascular cell adhesion molecule-1 (“VCAM-1”), as well as to the extracellular matrix protein fibronectin (“FN”). Ruegg, et al., J. Cell Biol., 177, p. 179 (1991); Wayner, et al., J. Cell Biol., 105, p. 1873 (1987); Kramer et al., J. Biol. Chem., 264, p. 4684 (1989); Gehlsen, et al., Science, 24, p. 1228 (1988). Anti-VLA4 monoclonal antibodies have been shown to inhibit VLA-4-dependent adhesive interactions both in vitro and in vivo. Ferguson, et al., Proc. Natl. Acad. Sci., 88, p. 8072 (1991); Ferguson, et al., J. Immunol., 150, p. 1172 (1993). Results of in vivo experiments suggest that the inhibition of VLA-4-dependent cell adhesion should prevent, inhibit or alter several inflammatory and autoimmune pathologies. R. L. Lobb, et al., J. Clin. Invest., 94, pp. 1722-28 (1994). See also Kabanov, et al., U.S. Pat. No. 6,656,459, for example, entitled Compositions of Non-Ionic Block Copolymers to Treat Autoimmune and Inflammatory Diseases, And To Reduce Graft/Implantation, and Methods of Use Thereof, issued Dec. 3, 2003.
Cell adhesion in tissues were minimized by use Polyethylene Glycol (PEG) to forming steric barrier between tissues. See WO9910022 issued Mar. 4, 1999 and WO9903481 issued Jan. 28, 1999. Crosslinking PEG and polyacids to form gels in inhibiting cell adhesion are disclosed in U.S. Pat. No. 6,869,938 to Schwartz et. al., Compositions of Polyacids and Polyethers and Methods for Their Use In Reducing Adhesions, issued Mar. 22, 2005. Crosslinked hyaluronic acid gels to inhibit cell adhesion is described in U.S. Pat. No. 6,630,167 to Zhang et. al., Hyaluronic Acid Anti-Adhesion Barrier, issued Oct. 7, 2003.
Hyaluronic acid gel compositions containing non-steroidal anti inflammatory drugs (NSAIDs) and excess of organic divalent metal salts including magnesium were used for prevention of adhesion and inflammation. Such compositions were found to have increased residence times in biological environments and in vivo animal studies reduced adhesion formation. See U.S. Pat. No. 6,037,331 to Shalaby et. al., Compositions For Prevention Of Inflammation And Adhesion Formation Uses Thereof, issued Mar. 1, 2000.
Magnesium has been found to act as a blocker of nerve cell. N-methyl-D-aspartate receptors (NMDAR) which activates neural sensitization. Thus neuropathic pain and its resultant inflammation was reduced. See M. Jones, “Chronic Neuropathic Pain: Pharmacological In The New Millennium”, International J. Pharmaceutical Compounding, January-February 2000.
Given the above, methods useful for increasing the efficiency of inhibition, alteration, or prevention of cell adhesion and cell adhesion-mediated pathologies are needed. For example, prevention and/or treatment of inflammatory and autoimmune diseases, and reduction of pain is needed in particularly post-surgery.